A Review of Intraoperative Goal-Directed Therapy Using Arterial Waveform Analysis for Assessment of Cardiac Output

Increasing evidence shows that goal-directed hemodynamic management can improve outcomes in surgical and intensive care settings. Arterial waveform analysis is one of the different techniques used for guiding goal-directed therapy. Multiple proprietary systems have developed algorithms for obtaining cardiac output from an arterial waveform, including the FloTrac, LiDCO, and PiCCO systems. These systems vary in terms of how they analyze the arterial pressure waveform as well as their requirements for invasive line placement and calibration. Although small-scale clinical trials using these monitors show promising data, large-scale multicenter trials are still needed to better determine how intraoperative goal-directed therapy with arterial waveform analysis can improve patient outcomes. This review provides a comparative analysis of the different arterial waveform monitors for intraoperative goal-directed therapy

A Review of Intraoperative Goal-Directed Therapy Using Arterial Waveform Analysis for Assessment of Cardiac Output

Increasing evidence shows that goal-directed hemodynamic management can improve outcomes in surgical and intensive care settings. Arterial waveform analysis is one of the different techniques used for guiding goal-directed therapy. Multiple proprietary systems have developed algorithms for obtaining cardiac output from an arterial waveform, including the FloTrac, LiDCO, and PiCCO systems. These systems vary in terms of how they analyze the arterial pressure waveform as well as their requirements for invasive line placement and calibration. Although small-scale clinical trials using these monitors show promising data, large-scale multicenter trials are still needed to better determine how intraoperative goal-directed therapy with arterial waveform analysis can improve patient outcomes. This review provides a comparative analysis of the different arterial waveform monitors for intraoperative goal-directed therapy

Totally endoscopic robot-assisted transmyocardial revascularization

ObjectiveLaser transmyocardial revascularization is an emerging therapy for intractable angina stemming from diffuse, small-vessel coronary disease not amenable to percutaneous coronary intervention or coronary bypass grafting. Presently, this therapy is delivered through a median sternotomy or left thoracotomy. In this pilot study, we sought to combine the advantages of a dexterous robotic surgical platform with a flexible fiberoptic laser to develop a minimally invasive approach toward transmyocardial revascularization.MethodsA flexible fiberoptic holmium:yttrium-aluminum-garnet laser probe (CardioGenesis Corporation, Foothill Ranch, Calif), deployed with the da Vinci surgical robotic system (Intuitive Surgical, Sunnyvale, Calif), was used to create transmyocardial channels through all left ventricular wall regions in 5 canine subjects. The channels were localized, quantified, and histologically analyzed to assess distribution, dimensions, and transmurality.ResultsTransmyocardial channels were successfully created in all 6 defined left ventricular wall segments by using this minimally invasive approach without port repositioning, instrument exchange, or probe modifications. Gross pathologic and histologic analyses confirmed the uniform distribution of 1.0-mm transmural channels in all left ventricular regions. No direct pressure, topical hemostatic agents, or suture repairs were required for hemostasis. No significant hemodynamic instability or sustained arrhythmias were encountered at any time during the procedures.ConclusionsWe report the first use of a prototype flexible fiberoptic laser probe deployed by the da Vinci surgical robotic system to successfully perform totally endoscopic off-pump transmyocardial revascularization in a canine model, demonstrating the feasibility, precision, and safety of this approach. Refinement of this minimally invasive technique may reduce the morbidity of open-chest transmyocardial revascularization and facilitate its use as sole therapy or as an adjunct to percutaneous coronary interventions

Characterization of Shiga toxin-producing Escherichia coli O130:H11 and O178:H19 isolated from dairy cows

Shiga toxin-producing E. coli (STEC) are isolated from human patients with bloody diarrhea, hemorrhagic colitis (HC), and hemolytic uremic syndrome (HUS). In the last years, the infections with non-O157 serotypes are increasing their frequency of association with human disease. STEC produce Shiga toxin (Stx) and other virulence factors that could contribute to human pathogenesis. Cattle are the main reservoir and the transmission to humans is through the consumption of undercooked meat, non-pasteurized dairy products, and vegetables or water contaminated with feces. We have previously determined that O130:H11 and O178:H19 serotypes were the most prevalent in dairy cows from Argentina. In the present study, 37 and 25 STEC isolates from dairy cows belonging to O130:H11 and O178:H19 serotypes, respectively, were characterized regarding to their cytotoxicity on Vero cells, stx subtypes, presence of saband typing by multiple-locus variable-number tandem repeat analysis (MLVA). All strains demonstrated a cytotoxic effect, and in O130:H11 isolates, stx2EDL933 was the predominant subtype. In O178:H19 isolates the main stx2 subtype was stx2vha. The sab gene was detected in 65 and 24% of the isolates belonging to O130:H11 and O178:H19, respectively. Only one MLVA profile was identified among the O130:H11 isolates meanwhile 10 MLVA profiles were detected among the O178:H19 isolates which were grouped in two main clusters. In conclusion, our data show that O130:H11 and O178:H19 STEC isolates encode virulence factors associated with severe human disease and both serotypes should be considered for routinely testing. Our subtyping experiments showed that isolates could be distinguished based on the stx2 subtype and the presence/absence of sabgene, and for isolates belonging to O178:H19, also when the MLVA type was considered. However, MLVA subtyping of O130:H11 isolates will require the development of more specific markers.Fil: Fernandez, Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; ArgentinaFil: Krüger, Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; ArgentinaFil: Polifroni, Rosana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; ArgentinaFil: Bustamante, Ana Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; ArgentinaFil: Sanso, Andrea Mariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; ArgentinaFil: Etcheverría, Analía Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; ArgentinaFil: Lucchesi, Paula Maria Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; ArgentinaFil: Parma, Alberto Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; ArgentinaFil: Padola, Nora Lía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; Argentin

Genetic characterization of Shiga toxin-producing Escherichia coli O26:H11 strains isolated from animal, food, and clinical samples

The Shiga-toxin producing Escherichia coli (STEC) may cause serious illness in human. Here we analyze O26:H11 strains known to be among the most reported STEC strains causing human infections. Genetic characterization of strains isolated from animal, food, and clinical specimens in Argentina showed that most carried either stx1a or stx2a subtypes. Interestingly, stx2a-positive O26:H11 rarely isolated from cattle in other countries showed to be an important proportion of O26:H11 strains circulating in cattle and food in our region. Seventeen percent of the isolates harbored more than one gene associated with antimicrobial resistance. In addition to stx, all strains contained the virulence genes eae-β, tir, efa, iha, espB, cif, espA, espF, espJ, nleA, nleB, nleC, and iss; and all except one contained ehxA, espP, and cba genes. On the other hand, toxB and espI genes were exclusively observed in stx2-positive isolates, whereas katP was only found in stx1a-positive isolates. Our results show that O26:H11 STEC strains circulating in Argentina, including those isolated from humans, cattle, and meat products, present a high pathogenic potential, and evidence that cattle can be a reservoir of O26:H11 strains harboring stx2a.Fil: Krüger, Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias; ArgentinaFil: Lucchesi, Paula Maria Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias; ArgentinaFil: Sanso, Andrea Mariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias; ArgentinaFil: Etcheverría, Analía Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias; ArgentinaFil: Bustamante, Ana Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias; ArgentinaFil: Burgán, Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias; ArgentinaFil: Fernandez, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias; ArgentinaFil: Fernandez, Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias; ArgentinaFil: Leotta, Gerardo Anibal. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Instituto de Genética Veterinaria "Ingeniero Fernando Noel Dulout"; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias; ArgentinaFil: Friedrich, Alexander W.. University of Groningen; Países BajosFil: Padola, Nora L.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias; ArgentinaFil: Rossen, John W. A.. University of Groningen; Países Bajo

Sur8, a determinant protein in colorectal cancer tumor progression

Resumen del trabajo presentado en el 43rd Annual Meeting of the SEBBM, celebrado en Barcelona (España) del 19 al 21 de julio de 2021.Colorectal cancer (CRC) has the highest incidence rate in the Spanish population. The most important challenge consists on the discovery of efficient disease treatments, due to high mortality rates in highly developed stages. Sur8 is a scaffold protein that positively modulates ERK signaling pathway, which has a major role in the progression and metastasis in colorectal cancer. The main goals of our research are to determine the role that Sur8 plays in the development and progression of CRC and to analyze its possible therapeutic potential. For this purpose, our group has developed an inducible conditional mouse model msur8f/fVillinCreERT2. In order to determine Sur8 action in the colonic tissue, we have developed organoids from the colon epithelium of healthy mice and have analyzed gene expression pattern by an RNAseq approach. Sur8 KO affects oncogenic CRC transcription factors expression, as well as the modulation of some Wnt pathway regulators. In regard to miRNA data, we have observed deregulation of miRNAs related to CRC in Sur8 KO organoids. To determine the role that Sur8 plays in the development and progression of CRC, we have subjected our inducible conditional mice to chemical carcinogenesis and we have observed that Sur8 KO males display less and smaller tumors and do not present any adenocarcinoma. In addition, we have carried out Sur8 silencing in human CRC cell lines by infection with constitutive shRNA lentiviruses. We have observed that Sur8 silencing produces decreases of cell tumor proliferation, and reduction of p-ERK levels. Finally, we are evaluating the effects of putative therapeutic agents against Sur8 in human CRC cell lines. Concretely, we are testing Celastrol, which has been described that binds and blocks the action of Sur8 in vitro. We have observed that Celastrol treatment diminishes the cell tumor proliferation in this model. Altogether, our results indicate that Sur8 may have a determinant role in CRC progression and that Sur8 could be a potential molecular target for the design of novel strategies against CRC

En búsqueda de la sustentabilidad y la recuperación del embalse San Roque

El mayor suministro de agua potable de la Ciudad de Córdoba y el Gran Córdoba proviene del Embalse San Roque. Su cuenca es la segunda región turística más importante de la Argentina y la principal de la provincia. El lago es utilizado como fuente de agua para consumo y recreación y como componente básico para la sustentabilidad económica de toda la región, por lo que resulta fundamental la adecuada administración de la cuenca por parte de la Gestión de Gobierno. En la última década, la presencia permanente de algas y la ocurrencia de eventos extremos de crecimiento han siendo percibidos de manera preocupante por los pobladores de las ciudades aledañas y los visitantes de la región. Recientemente han afectado el tratamiento de potabilidad destinada a la ciudad de Córdoba resultando una distribución de agua de mala calidad con olores y sabores desagradables. Asimismo el problema de algas y macrófitas ocurrido en la fuente natural a pocos días de iniciarse la Semana Santa en marzo de 2010, debió ser contrarrestado mediante la implementación de actividades de saneamiento consistente en la limpieza y extracción mecánica de la biomasa en sitios del río San Antonio y su desembocadura, el área del perilago más poblado. Ante los inminentes síntomas de eutrofización avanzada, se conformó el Grupo de investigación Interdisciplinario e Interinstitucional donde participan el Instituto Nacional del Agua, el grupo de investigación Biodiscos y el Laboratorio Central, División Agua y Efluentes de la Facultad de Ciencias Químicas - UCC; la Compañía de Ingenieros Paracaidistas IV y Batallón de Inteligencia de la Segunda División de Ejército - Ejército Argentino; la Facultad de Biología y el Instituto de Virología Vanella - UNC y la Secretaría de Ambiente de la Provincia de Córdoba, entre otras. El objetivo general es la realización de los estudios integrales del lago San Roque para diagnosticar su estado, con el fin de proponer a la Gestión de Gobierno las medidas de mitigación de los problemas y las correspondientes acciones de prevención y control.Fil: Bustamante, María Alejandra. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Welter, Adriana Beatriz. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Re, Viviana Elizabeth. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Grumelli, Yanina Alejandra. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Martínez Wassaf, Maribel Graciela. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Castillo, Jorge Eduardo. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Díaz Panero, Mariángeles. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Aguirre, Belquis Pamela. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentin

En búsqueda de la sustentabilidad y la recuperación del embalse San Roque

El mayor suministro de agua potable de la Ciudad de Córdoba y el Gran Córdoba proviene del Embalse San Roque. Su cuenca es la segunda región turística más importante de la Argentina y la principal de la provincia. El lago es utilizado como fuente de agua para consumo y recreación y como componente básico para la sustentabilidad económica de toda la región, por lo que resulta fundamental la adecuada administración de la cuenca por parte de la Gestión de Gobierno. En la última década, la presencia permanente de algas y la ocurrencia de eventos extremos de crecimiento han siendo percibidos de manera preocupante por los pobladores de las ciudades aledañas y los visitantes de la región. Recientemente han afectado el tratamiento de potabilidad destinada a la ciudad de Córdoba resultando una distribución de agua de mala calidad con olores y sabores desagradables. Asimismo el problema de algas y macrófitas ocurrido en la fuente natural a pocos días de iniciarse la Semana Santa en marzo de 2010, debió ser contrarrestado mediante la implementación de actividades de saneamiento consistente en la limpieza y extracción mecánica de la biomasa en sitios del río San Antonio y su desembocadura, el área del perilago más poblado. Ante los inminentes síntomas de eutrofización avanzada, se conformó el Grupo de investigación Interdisciplinario e Interinstitucional donde participan el Instituto Nacional del Agua, el grupo de investigación Biodiscos y el Laboratorio Central, División Agua y Efluentes de la Facultad de Ciencias Químicas - UCC; la Compañía de Ingenieros Paracaidistas IV y Batallón de Inteligencia de la Segunda División de Ejército - Ejército Argentino; la Facultad de Biología y el Instituto de Virología Vanella - UNC y la Secretaría de Ambiente de la Provincia de Córdoba, entre otras. El objetivo general es la realización de los estudios integrales del lago San Roque para diagnosticar su estado, con el fin de proponer a la Gestión de Gobierno las medidas de mitigación de los problemas y las correspondientes acciones de prevención y control.Fil: Bustamante, María Alejandra. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Welter, Adriana Beatriz. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Re, Viviana Elizabeth. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Grumelli, Yanina Alejandra. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Martínez Wassaf, Maribel Graciela. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Castillo, Jorge Eduardo. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Díaz Panero, Mariángeles. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Aguirre, Belquis Pamela. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentin

Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID‑19

Background. COVID-19 can course with respiratory and extrapulmonary disease. SARS-CoV-2 RNA is detected in respiratory samples but also in blood, stool and urine. Severe COVID-19 is characterized by a dysregulated host response to this virus. We studied whether viral RNAemia or viral RNA load in plasma is associated with severe COVID-19 and also to this dysregulated response. Methods. A total of 250 patients with COVID-19 were recruited (50 outpatients, 100 hospitalized ward patients and 100 critically ill). Viral RNA detection and quantification in plasma was performed using droplet digital PCR, targeting the N1 and N2 regions of the SARS-CoV-2 nucleoprotein gene. The association between SARS-CoV-2 RNAemia and viral RNA load in plasma with severity was evaluated by multivariate logistic regression. Correlations between viral RNA load and biomarkers evidencing dysregulation of host response were evaluated by calculating the Spearman correlation coefficients. Results. The frequency of viral RNAemia was higher in the critically ill patients (78%) compared to ward patients (27%) and outpatients (2%) (p < 0.001). Critical patients had higher viral RNA loads in plasma than non-critically ill patients, with non-survivors showing the highest values. When outpatients and ward patients were compared, viral RNAemia did not show significant associations in the multivariate analysis. In contrast, when ward patients were compared with ICU patients, both viral RNAemia and viral RNA load in plasma were associated with critical illness (OR [CI 95%], p): RNAemia (3.92 [1.183–12.968], 0.025), viral RNA load (N1) (1.962 [1.244–3.096], 0.004); viral RNA load (N2) (2.229 [1.382–3.595], 0.001). Viral RNA load in plasma correlated with higher levels of chemokines (CXCL10, CCL2), biomarkers indicative of a systemic inflammatory response (IL-6, CRP, ferritin), activation of NK cells (IL-15), endothelial dysfunction (VCAM-1, angiopoietin-2, ICAM-1), coagulation activation (D-Dimer and INR), tissue damage (LDH, GPT), neutrophil response (neutrophils counts, myeloperoxidase, GM-CSF) and immunodepression (PD-L1, IL-10, lymphopenia and monocytopenia). Conclusions. SARS-CoV-2 RNAemia and viral RNA load in plasma are associated with critical illness in COVID-19. Viral RNA load in plasma correlates with key signatures of dysregulated host responses, suggesting a major role of uncontrolled viral replication in the pathogenesis of this disease.This work was supported by awards from the Canadian Institutes of Health Research, the Canadian 2019 Novel Coronavirus (COVID-19) Rapid Research Funding initiative (CIHR OV2 – 170357), Research Nova Scotia (DJK), Atlantic Genome/Genome Canada (DJK), Li-Ka Shing Foundation (DJK), Dalhousie Medical Research Foundation (DJK), the “Subvenciones de concesión directa para proyectos y programas de investigación del virus SARS‐CoV2, causante del COVID‐19”, FONDO–COVID19, Instituto de Salud Carlos III (COV20/00110, CIBERES, 06/06/0028), (AT) and fnally by the “Convocatoria extraordinaria y urgente de la Gerencia Regional de Salud de Castilla y León, para la fnanciación de proyectos de investigación en enfermedad COVID-19” (GRS COVID 53/A/20) (CA). DJK is a recipient of the Canada Research Chair in Translational Vaccinology and Infammation. APT was funded by the Sara Borrell Research Grant CD018/0123 funded by Instituto de Salud Carlos III and co-fnanced by the European Development Regional Fund (A Way to Achieve Europe programme). The funding sources did not play any role neither in the design of the study and collection, not in the analysis, in the interpretation of data or in writing the manuscript

Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications

Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations.This work was supported by the Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Health (FIS; PI16/00425 and PI19/00321), Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER, 06/07/0036), IIS-FJD BioBank (PT13/0010/0012), Comunidad de Madrid (CAM, RAREGenomics Project, B2017/BMD-3721), European Regional Development Fund (FEDER), the Organización Nacional de Ciegos Españoles (ONCE), Fundación Ramón Areces, Fundación Conchita Rábago and the University Chair UAM-IIS-FJD of Genomic Medicine. Irene Perea-Romero is supported by a PhD fellowship from the predoctoral Program from ISCIII (FI17/00192). Ionut F. Iancu is supported by a grant from the Comunidad de Madrid (CAM, PEJ-2017-AI/BMD7256). Marta del Pozo-Valero is supported by a PhD grant from the Fundación Conchita Rábago. Berta Almoguera is supported by a Juan Rodes program from ISCIII (JR17/00020). Pablo Minguez is supported by a Miguel Servet program from ISCIII (CP16/00116). Marta Corton is supported by a Miguel Servet program from ISCIII (CPII17/00006). The funders played no role in study design, data collection, data analysis, manuscript preparation and/or publication decisions